Finally, COMT (catechol-O-methyltransferase), which modulates cortical dopamine levels, was the third most connecting 22q11.2-linked gene, following PRODH and DGCR6, in the adolescence stages. Recently, epistatic interaction between the PRODH and COMT genes was demonstrated at the level of transcription, in which selective up-regulation of COMT in the prefrontal cortex was shown to respond to enhanced dopaminergic signaling in PRODH-deficient mice [138]. Thus, individuals with both SZ and 22q11.2 deletion may have an additive disadvantage because they have deficits in both genes and therefore might not be able to compensate for reduced PRODH expression, for the cortical dopaminergic hyperactivity caused by PRODH deficiency. Our results showed significant enrichment of protein catabolic/metabolic activities in the adolescence stages, but not in the embryonic stage, supporting the critical roles of PRODH and COMT in the later stages of neural development (Fig. 7; Additional file 11).
